Perturbation of murine liver cyp-superfamily of isoforms by di different combinations of pesticide mixtures

It was previously found that fenarimol,vinclozolin or acephate,three of the most used pesticides worldwide,provoked a marked per- turbation of murine cytochrome P450 (CYP)-linked monooxygenases.Here,to more closely mimic human exposure,it was investigated whether di ?erent pesticide combinations administered i .p .in male Swiss Albino CD1 mice in single or repeated fashion (daily,for three consecutive days),a ?ect CYP-dependent oxidations.The four simulated mixtures showed a complex pattern of CYP induction and suppression,especially after repeated injection.For example,while fenarimol alone was the most inducing agent -reaching a 79-fold increase over control in testosterone 2 a hydroxylase -followed by vinclozolin and acephate,coadministration with the former markedly reduced induction.Coadministration with vinclozolin,determined various positive and negative modulations.An increase of CYP2B1/2 and CYP3A1/2-associated oxidases and a decrease of ethoxycoumarin metabolism was observed in the acephate and vinclozolin mixture. An equivalent or reduced CYP expression,if compared to double combinations,was seen using the complete mixture.Taken as a whole, the unpredictability of the recorded e ?ects with simple mixtures,shrinks the misleading extrapolation performed on a single pesticide.If reproduced in human,such changes,altering either endogenous metabolism or biotransformation of ubiquitous toxins,might have public health implications.